1. Field of the Invention
The invention relates generally to hypertonic fluid resuscitation compositions useful for treatment of circulatory and ischemic shock. The composition is a formulation which has particular ratios of sodium acetate/chloride. These formulations provide isochloremic resuscitation and improvements in acid base states which are especially beneficial in cases of large blood loss.
2. Description of Related Art
Circulatory shock is a common life threatening pathophysiological state which occurs secondary to trauma, hemorrhage, burns, sepsis, allergic reactions and heart failure. These different types of circulatory shock are characterized by reduced blood pressure and cardiac output. Furthermore, organ ischemia and inflammation are associated with certain procedures which can result in shock-like microcirculatory abnormalities. Both systemic shock and localized reactions cause a reduction in blood flow and oxygen delivery to vital organs and tissues. This low blood flow condition causes local hypoxia, ischemia, and can lead to loss of cellular and organ function and even death. Accepted definitive treatment for some types of circulatory shock and useful therapy in all types of shock are volume infusions.
The standard of care in initial management of hemorrhagic shock is rapid administration of large volumes of isotonic crystalloid solution, several liters in an adult patient. The preferred fluid is Ringer's lactate, although normal saline or other similar isotonic crystalloid solutions are also used. Recommended continued treatment is based on the observed response to the initial fluid therapy (American College of Surgeons, 1988). As a general rule, guidelines are based on the "three for one" rule. This is based on the long-standing empirical observation that most hemorrhagic shock patients require up to 300 ml of electrolyte solution for each 100 ml of blood lost.
Other isotonic fluid replacement solutions have been used, including isotonic crystalloid solutions mixed with macromolecular solutions of plasma proteins or synthesized molecules with similar oncotic properties (colloids); including albumin, dextran, hetastarch or polygelatin in 0.9% NaCl. Whole blood is also used, but it is expensive, often unavailable, carries some risk of viral infection and cross matching may delay therapy.
Crystalloids and colloids have been used as volume expanders, but generally must be infused in large volume. Such large volumes may cause peripheral and pulmonary edema. Additionally, the large volume requirements of isotonic fluids means that there are time delays and logistic difficulties associated with vascular delivery of effective therapy.
Hyperosmotic crystalloid and hyperosmotic/hyperoncotic (crystalloid/colloid) formulations offer some physiological benefits for the treatment of circulatory shock, including improved efficacy for restoration of overall cardiovascular function in animals and man compared to conventional resuscitation (Cone et al., 1987). Normalization of circulatory function has been obtained with such solutions (Kramer and Holcroft, 1990). Small volumes of salt/concentrated dextran formulations have been shown to rapidly restore and sustain normalization of circulatory function in hemorrhage (Kramer et al., 1986; Velasco et al., 1987). However, there remain some important limitations/side effects.
Small volume resuscitation of hypovolemic hemorrhage shock using 7.5 % NaCl solution (Nakayama et al., 1986; Bitterman et al., 1987; Muir et al., 1987) and a combination of 7.5 % NaCl and 6% Dextran-70 (Kramer et al., 1989 and 1990; Kreimeir et al., 1987, Velasco, et al., 1989) has been extensively studied. These studies have shown that HSD treatment results in a rapid improvement of blood pressure and near normalization of cardiac output, vital organ perfusion and O.sub.2 delivery when administered in volumes of 4-6 ml/kg to animals hemorrhaged 35-50 ml/kg. However, in patients with internal injury, pre-hospital resuscitation before surgical intervention may lead to increased bleeding as rapid rises in blood pressure re-open clotted and tamponaded vascular injuries. This phenomenon in uncontrolled hemorrhage has been demonstrated in different animals models in which mortality was increased subsequent to resuscitating with small volumes of HSD or large volumes of LRS (Bickell et al., 1991; Gross et al., 1988). The possibility that aggressive pre-hospital field resuscitation is more harmful than helpful has motivated recent trials in which all volume support is delayed until the start of surgery (Mattox et al. 1992).
In a recent examination of patients treated with either 7.5 % NaCl or LRS in the emergency room, no untoward effects on bleeding, neurological outcome, or cross-matching of blood were found, and there were no incidents of central pontine myelinosis (Vassar et al. 1990). There was, however, a significant hyperchloremic acidosis in 8 out of the 58 patients given HSD. While the acidemia in this study was attributed to the patients' pre-existing morbidity, a rapid decrease of pH in an already acidotic shock state could result in cardiac dysfunction (Onarheim et al., 1990; Walsch et al., 1991). Additionally, it was consistently found that a 4-6 ml/kg infusion of HSD in shocked animals was followed by an immediate decrease in pH of nearly 0.1 pH units (Kramer et al., 1986).
Hypertonic saline infusions in shocked animals and patients have been shown to cause an initial acidosis and hypokalemia. Treatment with hypertonic saline can also lead to a hyperchloremic acidosis, possibly due to excessive chloride load. Some isotonic Ringers solutions and mildly hypertonic formulations mimic sodium and chloride concentration ratios found in plasma and are thought to decrease the likelihood of acidosis (Fox, 1976). Circulatory shock is often associated with an acidosis and thus increased acidotic insult may be deleterious.
Although hypertonic saline rapidly improves both blood pressure and cardiac output, these beneficial effects may be overshadowed by deleterious effects from increased blood pressure. Uncontrolled internal bleeding in trauma patients may be aggravated by increased pressure, leading to increased bleeding. Return of normal blood pressure resulting in increased bleeding due to arterial pressure increase may lead to increased mortality over no treatment. Therefore, ideal pre-hospital resuscitation would increase cardiac output but only modestly increase blood pressure.
Another aspect of resuscitation fluids is their use under less than ideal (non hospital) conditions. Logistic restraints may severely curtail transportation of weighty or voluminous material. In battlefield situations it may be impractical to administer large volumes, yet there is a critical need to rapidly restore oxygen delivery to critical organs and to prevent or reverse the effects of traumatic shock.